Conjugates of a polymer, a bisphosphonate and an anti-angiogenesis agent and uses thereof in the treatment and monitoring of bone related diseases

Abstract

Conjugates of polymers or copolymers having attached thereto an anti-angiogenesis agent and a bisphosphonate bone targeting agent, and processes of preparing same, are disclosed. Pharmaceutical compositions containing these conjugates and uses thereof in the treatment of bone related disorders are also disclosed.

What is claimed is: 
     
       1. A conjugate comprising a polymeric backbone derived from polyglutamic acid (PGA) and comprising a plurality of backbone units covalently linked to one another, wherein a portion of said plurality of backbone units has an anti-angiogenesis agent attached thereto, and another portion of said plurality of backbone units has a bisphosphonate bone targeting moiety attached thereto, the conjugate being represented by the general formula I:
   [A 1 ]x[A 2 -L 1 -B]y[A 3 -L 2 -D]w  Formula I
 
 wherein: 
 x is an integer having a value such that x/(x+y+w) multiplied by 100 is in the range of from 70 to 99.8; 
 y is an integer having a value such that y/(x+y+w) multiplied by 100 is in the range of from 0.1 to 15; and 
 w is an integer having a value such that w/(x+y+w) multiplied by 100 is in the range of from 0.1 to 15, 
 A 1 , A 2  and A 3  are each backbone units covalently linked to one another and forming said polymeric backbone, wherein: 
 B is said anti-angiogenesis agent; 
 D is said bone targeting moiety; and 
 each of the L 1  and L 2  is independently a linker or absent; 
 such that [A 2 -L 1 -B] is a backbone unit having attached thereto said anti-angiogenesis agent; and 
 [A 2 -L 2 -D] is a backbone unit having attached thereto said bone targeting moiety; 
 wherein each of the [A 1 ], the [A 2 -L 1 -B] and the [A 3 -L 2 -D] is either a terminal backbone unit being linked to one of the [A 1 ], the [A 2 -L 1 -B] and the [A 3 -L 2 -D], or is linked to at least two of the [A 1 ], the [A 2 -L 1 -B] and the [A 3 -L 2 -D], whereby A 1 , A 2  and/or A 3  are linked to one another to thereby form said polymeric backbone. 
 
     
     
       2. The conjugate of  claim 1 , wherein said anti-angiogenesis agent is paclitaxel. 
     
     
       3. The conjugate of  claim 1 , wherein said bisphosphonate is alendronate. 
     
     
       4. The conjugate of  claim 1 , wherein at least one of L 1  and L 2  is a linker. 
     
     
       5. The conjugate of  claim 4 , wherein said linker is an enzymatically-cleavable linker. 
     
     
       6. The conjugate of  claim 5 , wherein said enzymatically-cleavable linker is cleaved by an enzyme which is overexpressed in tumor tissues. 
     
     
       7. The conjugate of  claim 6 , wherein said enzyme is selected from a group consisting of Cathepsin B, Cathepsin K, Cathepsin D, Cathepsin H, Cathepsin L, legumain, MMP-2 and MMP-9. 
     
     
       8. The conjugate of  claim 1 , wherein said anti-angiogenesis agent is attached to L 1  or to A 2  via a spacer. 
     
     
       9. The conjugate of  claim 4 , wherein said bisphosphonate is attached to L 2  or to A 3  via a spacer. 
     
     
       10. The conjugate of  claim 8 , wherein said anti-angiogenesis agent is paclitaxel and said paclitaxel is linked to L 1  or to A 2  via said spacer. 
     
     
       11. The conjugate of  claim 10 , wherein said spacer is p-aminobenzyl carbonate (PABC). 
     
     
       12. A conjugate having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         x is an integer having a value such that x/(x+y+w) multiplied by 100 is in the range of from 70 to 99.9; 
         y is an integer having a value such that y/(x+y+w) multiplied by 100 is in the range of from 0.01 to 15; and 
         w is an integer having a value such that w/(x+y+w) multiplied by 100 is in the range of from 0.01 to 15. 
       
     
     
       13. The conjugate of  claim 1 , further comprising a labeling agent attached thereto. 
     
     
       14. A pharmaceutical composition comprising, as an active ingredient, the conjugate of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       15. The pharmaceutical composition of  claim 14 , being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a bone related disease or disorder. 
     
     
       16. The pharmaceutical composition of  claim 14 , wherein said conjugate comprises a labeling agent, the composition being packaged in a packaging material and identified in print, in or on said packaging material, for use in monitoring a bone related disease or disorder. 
     
     
       17. A method of treating a bone related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the conjugate of  claim 1 . 
     
     
       18. A method of monitoring a bone related disease or disorder in a subject, the method comprising:
 administrating to the subject the conjugate of  claim 13 ; and 
 employing an imaging technique for monitoring a distribution of the conjugate within the body or a portion thereof. 
 
     
     
       19. The method of  claim 17 , wherein said disease or disorder is selected from the group consisting of bone metastases and bone cancer. 
     
     
       20. The method of  claim 18 , wherein said disease or disorder is selected from the group consisting of bone metastases and bone cancer. 
     
     
       21. A process of preparing the conjugate of  claim 1 , the process comprising:
 (a) co-polymerizing a plurality of monomeric units of said polymeric backbone, wherein a portion of said plurality comprises monomeric units terminating by a first reactive group, and another portion of said plurality comprises monomeric units terminating by a second reactive group, to thereby obtain a co-polymer comprising a polymeric backbone that comprises a plurality of backbone units, wherein a portion of said backbone units has said first reactive group and another portion of said backbone units has said second reactive group, said first reactive group being capable of reacting with said anti-angiogenesis agent and said second reactive being capable of reacting with said bisphosphonate; 
 (b) reacting said co-polymer with said anti-angiogenesis agent or with a derivative thereof, via said first reactive group, to thereby obtain said co-polymer having said anti-angiogenesis agent attached thereto; and 
 (c) reacting said co-polymer with said bisphosphonate or a derivative thereof, via said second reactive group, to thereby obtain said co-polymer having said bisphosphonate attached thereto, 
 thereby obtaining the conjugate of  claim 1 . 
 
     
     
       22. The conjugate of  claim 12 , further comprising a labeling agent attached thereto.